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J. Biol. Chem., Vol. 278, Issue 44, 42774-42784, October 31, 2003

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Cholesterol and Cholate Components of an Atherogenic Diet Induce Distinct Stages of Hepatic Inflammatory Gene Expression^*

Laurent Vergnes, Jack Phan, Merav Strauss, Sherrie Tafuri¶, and Karen Reue||

From the Departments of Medicine and Human Genetics, UCLA, Los Angeles, California 90095, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, and ^¶Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105

Atherosclerosis in inbred mouse strains has been widely studied by using an atherogenic (Ath) diet containing cholesterol, cholic acid, and fat, but the effect of these components on gene expression has not been systematically examined. We employed DNA microarrays to interrogate gene expression levels in liver of C57BL/6J mice fed the following five diets: mouse chow, the Ath diet, or modified versions of the Ath diet in which either cholesterol, cholate, or fat were omitted. Dietary cholesterol and cholate produced discrete gene expression patterns. Cholesterol was required for induction of genes involved in acute inflammation, including three genes of the serum amyloid A family, three major histocompatibility class II antigen genes, and various cytokine-related genes. In contrast, cholate induced expression of genes involved in extracellular matrix deposition in hepatic fibrosis, including five collagen family members, collagen-interacting proteins, and connective tissue growth factor. The gene expression findings were confirmed by biochemical measurements showing that cholesterol was required for elevation of circulating serum amyloid A, and cholate was required for accumulation of collagen in the liver. The possibility that these gene expression changes are relevant to atherogenesis in C57BL/6J mice was supported by the observation that the closely related, yet atherosclerosis-resistant, C57BL/6ByJ strain was largely resistant to dietary induction of the inflammatory and fibrotic response genes. These results establish that cholesterol and cholate components of the Ath diet have distinct proatherogenic effects on gene expression and suggest a strategy to study the contribution of acute inflammatory response and fibrogenesis independently through dietary manipulation.

Received for publication, June 9, 2003 , and in revised form, August 14, 2003.

^* This work was supported by National Institutes of Health Grants HL58627 and HL28481 (to K. R.) and the Philippe Foundation, Inc. (to L. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table I.

^|| To whom correspondence should be addressed: 11301 Wilshire Blvd., Bldg. 113, Rm. 312, Los Angeles, CA 90073. Tel.: 310-478-3711 (ext. 42171); Fax: 310-268-4981; E-mail: Reuek{at}ucla.edu.

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